6-(indan - 2 - amino - 2 - carboxamido) and 6 - (1,2,3,4 - tetrahydronaphthalene - 2-amino - 2 - carboxamido) penicillanic acids



United States Patent 3,494,915 6-(INDAN 2 AMINO 2 CARBOXAMIDO) AND 6 (1,2,3,4 TETRAHYDRONAPHTHALENE 2- AMINO 2 COXAMIDO) PENICILLANIC ACIDS Harvey E. Alburn, West Chester, Donald E. Clark, Norristown, Norman H. Grant, Wynnewood, and Peter B. Russell, Villanova, Pa., assignors to American Home Products Corporation, a corporation of Delaware N0 Drawing. Filed July 28, 1967, Ser. No. 656,669 The portion of the term of the patent subsequent to July 4, 1984, has been disclaimed Int. Cl. (107d 99/16; A61k 21/00 US. Cl. 260-2391 3 Claims ABSTRACT OF THE DISCLOSURE The compounds are 6-(indan-2-amino-2-carboxamido) and 6-(1,2,3,4-tetrahydronaphthalene-Z-amino-Z-carboxamido)penicillanic acids which have improved antibiotic activity, particularly against gram-positive strains of bacteria.

SUMMARY OF THE lNVENTION This invention relates to new synthetic penicillins having potent activity against gram-negative and gram-positive micro-organisms, and particularly the latter.

The new synthetic penicillins of the present invention, when considered in their broadest aspects, include those compounds encompassed within the following structural formula:

wherein R and R each may be selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl and aryloxy; and n is an integer from 1 to 2.

The novel compounds of the invention may generally be prepared by reacting a suitable 4-substituted 2,5- oxazolidinedione (also known as an N-carboxy amino acid anhydride or NCA) with 6-amino penicillanic acid (6-APA). Preferably, a solution of 6-APA and triethylamine is first prepared which is slightly acid (e.g., pH 6). Thereafter the selected N-carboxy anhydride is added, and the reaction mixture stirred at room temperature. The novel compounds of the invention, resulting from the reaction between 6-APA and the N-carboxy amino acid anhydride may then be recovered by conventional procedures such as filtration, concentration, water extraction and precipitation from organic solvents, as indicated.

The N-carboxy amino acid anhydrides suitable for preparing the new penicillins of Formula I above when n is l; i.e. the Z-aminoindane-Z-carboxylic acid NCAs, may be prepared by a synthesis which starts with the preparation, from a selected indene, of the corresponding Z-indanone by the method described by Rose, Dorfman and Linfield in the Journal of Organic Chemistry 29, 1793, 1964. The hydantoin of the Z-indanone may then be prepared by the generally known method of reacting the Z-indanone with ammonium carbonate and potassium cyanide in an organic solvent. The resulting Z-indanone hydantoin may then be transformed to the Z-aminoindane-Z-carboxylic acid by ring splitting hydrolysis, as by heating in the presence of barium hydroxide. Finally, the NCA of the resulting Z-amino-indane-Z-carboxylic acid may be prepared by the phosgenation of said acid.

3,494,915 Patented Feb. 10, 1970 The N-carboxy amino acid anhydrides suitable for use in the preparation of the novel penicillanic acid compounds of this invention may also be prepared by other known procedures such as those referred to or described, for example, in US. Patent No. 3,194,802 of H. E. Alburn, N. H. Grant and H. Fletcher III.

The N-carboxyanhydrides suitable for preparing the new penicillins of Formula I wherein n is 2; i.e., the 1,2,3,4-tetrahydronaphthalene-Z-amino-2-carboxylic acid NCAs, may be prepared by a general synthesis similar to that set forth above, with merely the substitution of a selected 1,2,3,4-tetrahydronaphthalene for the indene starting material of the first synthesis.

The foregoing general synthesis may be represented schematically as follows:

wherein R R and n, each has the same meaning as set forth with respect to Formula I above, and Z is a trivalent hydrocarbon of the group consisting of:

II H -CH and CH2-CH The new penicillin compounds of the series defined above show desirable broad spectrum antibacterial activity and are useful as therapeutic agents for poultry and mammals in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, and of surprisingly greater activity with respect to the former, and particularly strains of Streptococcus and Staphylococcus, by either parenteral or oral administration. They also have use as nutritional supplements in animal feed.

As will be understood by those skilled in the art, the penicillin compounds of the invention may be utilized in their acid form or in the form of the therapeuticallyactive salts thereof, e.g., the sodium or potassium salts, or hydrochloride, sulfate, fumarate, etc., or in the form of the pharmaceutically-acceptable acid addition salts prepared by the reaction of the penicillin compounds with an amine or diamine base, e.g., procaine or various N-N'-disubstituted alkylene diamines, such as N,N'-dibenzylethylene-diamine, etc.

As will also be understood by those skilled in the art, the compounds of the invention may be utilized in suitable dosage forms, including solutions, suspensions, tablets, capsules, and the like, utilizing conventional solvents, suspensoids, excipients, and the like.

The following examples are illustrative of the in-ven- 3 4 tion, but are not to be considered necessarily limitative raised to 90 C. The temperature was maintained at thereof: 90 C. for 2 hours as phosgene was bubbled into the solu- EXAMPLE I tion. The phosgene was stopped and the reaction was u flushed with dry nitrogen at room temperature overnight. 6(mdan'z'ammo'zcal'hoxamldo)Pehlclhahlc held The solvent was removed in vacuo and the residue was (A) Preparation f 2-i d 325 1 f 99% f triturated with hexane, and filtered. Yield: 12.0 gms., mic acid, 43 1 of vWater, and 70 1 f 30% hydrogen 89% M.P. 123-125 C. This was recrystallized from ethyl peroxide were mixed and warmed to 35 C. over fifteen acetate-hemm- Yieldi 8 1 -157 C- minutes. Freshly distilled indene (58.1 gms.) was added 6'ihdah 2 amino 2 mp i lover 2 hours while maintaining a temperature of 3436 C. lanic acid-Five grams of y- With a cool water bath. The mixture was stirred an adcarhoxyhc acid ahhydride Was added With stirring to a ditional hour at 3436 C. and then overnight at room Solution Containing gIIlS- 0f 6APA in 100 m f temperature, water adjusted to pH 6.0 with triethylamine. The reac- 10 6 gms, of th heptahydrate f ferrous lf t were tion mixture was stirred overnight at room temperature, added in 53 ml. of water to e o th active Oxygen then adjusted to pH 5.0 and the insoluble product colcompounds and the solution was concentrated to 170 ml. lected- After drying in VaCuO at room temperature, it in vacuo. A solution of 140 ml. of concentrated H 50 Weighed in 860 ml. of Water was added and 200 ml. of distillate for 1a 21 3 4 2 H, was steam distilled. The distillate was extracted with 3X 100 ml. of methylene chloride. The extracts were combined and washed with 500 ml. of Water, dried over EXAMPLE H Na SO filtered, and evaporated to an oil which crystal- FOHOWlhg the Procedures of EXamPh? the P- 1i d p 57 59 C 67% propriate 2-indanones, or l,2,3,4-tetrahydro-naphtha- (B) Preparation of Z-indanone hydantoin.2-indanone, hhhes, and the Corresponding hydamoins, Carhoxyhc 225 gms, (0,17 l ammonium carbonate, h acids, and ultimate N-carboxy amino acid anhydrides drate 48.5 grns. (0.425 mole), and potassium cyanate thereof, Were Prepared, and the latter, as given in Table 16.3 gms. (0.25 mole) were mixed in 210 ml. of forma- A below, were respectively reacted with 6APA to obtain mide and heated in a pressure bomb at 100 C. overnight. the respective penicillin products also given in the the The cooled reaction was diluted with 600 ml. of water table.

TABLE A Penicillanic Acid Product formed 2-8min0-12,3,4-tetrahydro-fi-methoxy-Q-naphthoic acid 6-(2-amino-1,2,3,4-1;etrahydro'frmethoxy-2-nflphthfltllld0)DQIECIHQIUC acid. 2-amino-1,2,3,4-tctrahydrd7-ethoxy-Q-naphthoic acid 6-(2-amin01,2,3,4-tatrahydro-7-ethpxy-2-naphthamido)pcnicillan c ac d. Z-amino-l,2,3,4-tetrahydro-3,6dimethyl-2-naphtholc ac 6-(2-amino-1,2,3,4-tetrahydro-3,6-dimethyl-Z-naphtharmdo)pcniclllanic acid. 2-amin04-phenyl-2-indancarboxylic acid 6-(In an-z-amino-e henyl-zcarboxamrdp)pcnic llamcacld 2-amin0-3-phen0xy-Z-indancarboxylic acid 6-(Indan-2-amino-3-phenow-2-carboxarnido)pc uclllanieacid. 2-amino-4-buty1-2-indancarboxylic acid 6-(Indan-2-amln0-4-butyl-Z-cill'bOXfiDlldO){36111011181110 acid.

N-Carboxy Amino Anhydride 0fand acidified with concentrated HCl to pH 2 with good We claim: ventilation. The precipitate was filtered, washed with 1. A compound having the formula: water and dried. M.P. 2557 C. Yield: 46.5 gms. Wet. 1 2 s OH; The material was purified by dissolving in 5% aqueous NH? NaOH, extracting with ether, and acidified. M.P. 260- C (|3N H CH2 (|)H H3 2 2 c NCHCOOH (C) Preparation of 2-aminoindane-Z-carboxylic acid. 2-1ndanone hydantoin 55.75 gms. (0.273 mole), barium whersin R1 and R2 are each Selected from the group com hydroxide octahydrate 215 ms. (0.685 mole) and 300 o sistin of hydrogen, lower alkyl, lower alkoxy, phcnyl ml. of water were heated in a bomb at 200 C. for 20 and g y; and n is an integer from 1 to 2' hours. The pressure reached 250 p.s.i. The hydrolysis mixture was acidified with concentrated HCl to pH 2, (fompound as defined m clalm whlch com heated to boiling, treated with Darco G-60 and filtered. Poun.

6-(1nd1an 2 amino 2 carboxamido)pen1c1llan1c 38 ml. of concentrated H 50 was added to the filtrate with stirring and the slurry was heated and filtered. The am fi 1 h BaSO precipitate was washed with hot water and the A c9mpound as de ned m alm w ere repre' combined filtrates were evaporated to dryness. The residue sents the Integer was dissolved in 100 ml. of Water and adjusted to pH 4.5 R f C1 d with aqueous NaOH and chilled. The product was dried. e erences l e A second crop was obtained by concentrating the mother UNI ED STATES PATENTS q 3 329 675 7/1967 Alb t 1 260-2391 Yield: 1st crop, 12.2 gins; M.P. 309-311 C.; 2nd crop I um e a n u 2 Total, g 33%. NICHOLAS S. RIZZO, Primary Examiner (D) Preparation of 2-am1no1ndane 2 carboxylic acid NCA.2-aminoindane 2 carboxylic acid 11.9 grns. US. C1.X.R.

(0.068 mole) was stirred in 250 ml. of anhydrous dioxane, 424271 and phosgene was introduced as the temperature was @33 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent NO. 3, L9 L,915 DatedFebruary 1o 197o Inventor(s) Harvey E. Alburn et a1 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as show! below:

' In column 2, lines 16-20, formula II, which appears as follows:

II II should read:

In column t, line 3, (claim 2) "indian" should read -inda.n-.

SIGNED ANT SEALED swam AM J ndwardllflm A Ir mmz. JR-

nestm offim Commissioner of Patents 

